Opinion TRENDS in Genetics Vol.17 No.
7 July 2001 383
How do
mitochondrial genes
get into the nucleus?
Katrin Henze and William Martin
It is well known that genes from chloroplasts and mitochondria were
transferred to the nucleus many times during plant evolution. But in what form
do the transferred genes physically make that intracellular journey – as RNA,
as cDNA, as pieces of organelle DNA, or as whole organelle chromosomes?
Current views focus upon cDNA as the vehicle, based upon some examples
from plants. But other mechanisms, involving direct transfer of DNA from
organelle chromosomes, could also account for the available data. Direct DNA
transfer, rather than cDNA-mediated transfer, does occur today, and it probably
prevailed during the early phases of organelle evolution.
The evolution of plastids and mitochondria entailed
the transfer of genes from organelles to the nucleus.
Study of this topic goes back about 20 years,
beginning with the discovery of recombined
mitochondrial chromosome segments in nuclear
DNA1,2. Examples of DNA transfer from plant
mitochondria were subsequently found3,4 that
suggest some genes might be transferred to the
nucleus as cDNA (i.e. as double-stranded reverse-
transcribed mitochondrial mRNA).
The evidence supporting the view that cDNA
might be involved primarily comes from the findings
that integrated nuclear copies of genes that stem
from plant mitochondria often lack the introns that
their mitochondrial copies in related species possess.
In addition, the nuclear copies are sometimes
more similar to edited mitochondrial mRNAs than
they are to the genes encoded in the mitochondrial
DNA itself3–6. Furthermore, genes from plant
mitochondrial DNA have been transferred to the
nucleus multiple times in independent lineages,
a good example being the rps10 gene that encodes
a protein of the mitochondrial ribosome. Some
years ago, Volker Knoop showed that the rps10 gene
is present in the mitochondrial genome of some
flowering plants (angiosperms), but located in the
nucleus of others5. A recent paper extended those
findings, reporting rps10 in the nucleus of numerous
other angiosperm lineages6 and underscoring the
view that gene transfer from organelles to the
K. Henze nucleus is an active, prevalent and ongoing
W. Martin*
Institute of Botany III,
evolutionary process.
Universität Düsseldorf, These developments raise the important
Universitätsstraße 1, question: how do genes actually relocate from
D-40225 Düsseldorf,
organelles to the nucleus during evolution? Here
Germany.
*e-mail: w.martin@ we consider the evidence that mitochondrial genes
uni-duesseldorf.de are transferred to the nucleus through reverse
http://tig.trends.com 0168–9525/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0168-9525(01)02312-5
transcription of spliced and edited mitochondrial
mRNA into cDNA, and we examine whether
other mechanisms involving direct transfer of
chromosomal DNA might also account for the same
observations. A particularly striking example of
direct DNA transfer – the massive 620-kb DNA
chunk of mitochondrial DNA in the nucleus of
Arabidopsis – features prominently in this
discussion.
Editing
RNA editing is widespread in plant mitochondria.
It usually involves the conversion of uracil residues
in the mitochondrial primary RNA transcripts into
cytosine residues (U→C editing) so that the proper
amino acid is specified by the respective codon in the
resulting mRNA, although C→U editing also occurs7.
The biochemical mechanisms of plant mitochondrial
editing are still not known, and many questions
remain about the evolutionary dynamics of
mitochondrial editing across different plant
lineages and even across genes within the same
mitochondrion7,8. For example, in the sequenced
Arabidopsis mitochondrial genome9 there are
441 C→U editing sites8. These sites have a density of
about 14 per kb in protein-coding regions, one per kb
in introns, 0.5 per kb in 5′- and 3′-untranslated
regions, and none in tRNAs, rRNAs and noncoding
regions8. But even within these coding regions,
editing density ranges from no sites in the 1.5-kb cox1
gene to 39 sites in the 620-bp ccb2 gene8. No obvious
consensus sequences are associated with edited
sites8, and worse, the phylogenetic distribution of
mitochondrial editing across various land-plant
lineages is highly erratic, showing both gene-specific
and lineage-specific patterns.
If mitochondrial copies of a gene contain edited
sites when the nuclear copies of the same gene
lack them, does this mean that the gene must have
been transferred through an mRNA intermediate
(Fig. 1a)? No, not really, because it is also possible
that the gene was transferred at a time when the
sites in question were not edited (Fig. 1b). In the
plant kingdom, mitochondrial editing has not
been found in algae, so we can assume it to be an
invention of the higher plants, where it is reasonably
(but not uniformly) widespread. If a gene was
transferred to the nucleus in one plant lineage
before mitochondrial editing evolved but remained
in the organelle in other lineages where editing
arose, the nuclear copy would appear more similar
to an edited transcript than to the remaining
mitochondrial copies at the edited sites (Fig. 1b).
However, the same observation is taken as evidence
for cDNA-mediated transfer.
Because editing shows very erratic patterns of
taxon-specific occurrence even among higher-plant
lineages7,8, either editing (and/or specific edited
sites) arose independently in many higher-plant
lineages, or editing was universal among ancestral
384 Opinion TRENDS in Genetics Vol.17 No.7 July 2001

Fig. 1. Integration of
mitochondrial genes
(a) Reverse transcription and integrative (c) Direct transfer and integration of transiently
into the nuclear DNA:
mechanisms that appear recombination of cDNA unedited and intronless mtDNA
as though a cDNA P TrP
intermediate was involved.
nuDNA TT T T T T P TrP
AA A A A A nuDNA TT T T T T
(a) A cDNA-mediated AA A A A A
model entailing reverse
Transfer
transcription of a spliced
Recombination
and edited mitochondrial
transcript that becomes cDNA TT T T T T
AA A A A A nuDNA TT T T T T
integrated in the nucleus. AA A A A A
(b) A mechanism involving Reverse transcription
direct transfer of mtDNA,
mRNA UU U U U U
whereby editing and
introns arise in the Transfer
mitochondrion later. Splicing and editing
(c) A mechanism involving
direct transfer of mtDNA, RNA CC C C C C
whereby editing and mtDNA
TT T T T T
AA A A A A
introns in the Transcription
mitochondrion come and
go during evolution. Recombination
mtDNA CC C C C C
Boldface lettering indicates GG G G G G cDNA TT T T T T
AA A A A A
the nuclear DNA (nuDNA)
and mitochondrial DNA
Reverse transcription
(mtDNA) that would exist (b) Direct DNA transfer and integration prior
today, and hence be to the origin of editing and introns in mtDNA mRNA UU U U U U
analysed in the laboratory
(the observation). Note P TrP Splicing and editing
nuDNA TT T T T T
that, although the
AA A A A A
mechanisms and
RNA CC C C C C
underlying processes are
different, the observations Recombination
are identical in all three nuDNA Transcription
TT T T T T
panels. C→U edited sites AA A A A A

and introns (orange mtDNA CC C C C C

GG G G G G
triangles) are indicated.
Note that in panel (c),
Transfer mtDNA CC C C C C
GG G G G G
any of the mtDNA
Introduction of introns and edited sites into mtDNA
Introduction of introns and edited sites into mtDNA

intermediates could be mtDNA CC C T C C

transferred, but that the GG G A G G

topmost in the panel mtDNA CC C T C C

would have the highest GG G A G G

likelihood of giving rise mtDNA CC C T C T

to a nuclear gene with a GG G A G A
fuctional gene product.
mtDNA CC C T C T
Recent findings provide GG G A G A
strong evidence that direct
transfer of mtDNA as mtDNA CT C T C T
GA G A G A
indicated in (b) and (c) is mtDNA CT C T C T
quite common in higher GA G A G A
plants, given that a whole
mitochondrial genome mtDNA TT C T T T
was found integrated into AA G A A A
mtDNA TT C T T T
in the Arabidopsis nuclear AA G A A A

chromosomes.
mtDNA TT T T T T
AA A A A A
mtDNA TT T T T T
AA A A A A
TRENDS in Genetics

higher-plant lineages, but some process exists land-plant mitochondria7. Under the influence of
that removes edited sites from mitochondrial editing, reverse transcription and homologous
DNA (Fig. 1c). recombination of mitochondrial transcripts, or
One way to remove editing from mitochondrial with the help of reverse editing, a hypothetical
DNA would be reverse transcription of edited mRNA evolutionary equilibrium of the edited state
and recombination back into the mitochondrial versus the unedited state for a given site in the
genome, which could proceed through homologous mitochondrial DNA would result (Fig. 1c). In this
recombination in the organelle (Fig. 1c). Another case, direct transfer of mitochondrial DNA without a
way would be U→C edits in addition to typical cDNA intermediate could easily occur. Furthermore,
C→U edits, and this process is found in some lower although direct DNA transfer of any intermediate

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Opinion TRENDS in Genetics Vol.17 No.7 July 2001
state could occur, only transfers of the unedited
state would have a chance of successfully
substituting the function of the mitochondrial copy,
because genes with edited sites could not be decoded
by the nuclear–cytoplasmic gene-expression
machinery. Clearly, this scenario requires the
existence of mechanisms that remove edited sites
in mitochondrial DNA.
Both in the case of transfer of a gene before the
origin of editing (Fig. 1b) and in the case of transfer of
transiently unedited genes during evolution (Fig. 1c),
a sequence comparison would show that the nuclear
copy of mitochondrial origin (designated in boldface
type as nuDNA in Fig. 1) is more similar to the
edited transcript than to a mitochondrial gene that
possesses edited sites (boldface mtDNA in Fig. 1).
Until now, this type of observation has been taken
as evidence that the transfer mechanism of plant
mitochondrial DNA to the nucleus proceeded through
a cDNA intermediate (Fig. 1a). But Fig. 1b and Fig. 1c
both show mechanisms of gene transfer that produce
exactly the same observation even though they do not
involve the transfer of a cDNA, rather bulk DNA is
transferred from the mitochondrial genome.
Introns
If the mitochondrial copy of a gene contains introns
when the nuclear copies of the same gene lack them,
does this mean that the gene must have been
transferred through an mRNA intermediate? Not
necessarily, because it is also possible that the gene
was transferred at a time when it did not possess the
intron. There is evidence that plant mitochondrial
introns can be mobile, in particular the rps10 intron,
which is clearly related to both the second intron of
the mitochondrial cox3 gene and the intron in the
gene for 26S ribosomal RNA of Marchantia5,10. The
rps10 intron is missing in the mtDNA of some plant
lineages1, including those recently surveyed, where
it even cropped up in one mtDNA lineage (carrot)
without the flanking exons6. Here again, it is possible
that transfer to the nucleus could have occurred
without a cDNA intermediate. It is even conceivable
that the rps10 intron was removed after transfer to
the nucleus, perhaps in the same manner that the
normal GT–AG introns of eukaryotes are thought to
have been lost; that is, through splicing of the nuclear
transcript, reverse transcription and recombination
in the nuclear DNA11. In the case of self-splicing
introns, this would not require any auxiliary factors,
so splicing of a transcript generated outside the
confines of the mitochondrion would, in principle,
be possible. As in the case of editing, it seems that
introns do not provide compelling evidence that the
transfer mechanisms involve cDNA rather than
direct DNA transfer.
Evidence for direct DNA transfer
Is there any good, hard evidence for direct
wholesale transfer of mitochondrial DNA to the
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385
nucleus that does not involve a cDNA intermediate?
Yes. By far the most eye-opening organelle-to-
nucleus transfer yet observed is an entire
mitochondrial genome that cropped up on
chromosome 2 of the Arabidopsis genome12,13. This
chunk of mitochondrial DNA in the Arabidopsis
nucleus –referred to here as c2mtch (for
chromosome 2 mitochondrial-DNA chunk) – was
initially estimated12 to comprise fully 75% of the
366924-bp Arabidopsis mitochondrial genome9.
However, a recent more-detailed study13 using
in situ hybdridization showed that c2mtch in fact
represents an entire mitochondrial genome – and
then some! It seems that Arabidopsis contig-
assembly computers missed a detail or two, and
that c2mtch is not 270 kb, but ~620 kb long. This
is longer than the Arabidopsis mtDNA itself, the
additional length coming from internal duplications
of large segments of this complete mtDNA genome,
which might have occurred while the molecule
was still in the mitochondrion13. Clearly, c2mtch
was inserted (recombined) into chromosome 2
as a single contiguous piece of mitochondrial
chromosomal DNA12,13 – introns, tRNAs, noncoding
regions and all – indicating that it simply stems
from a lysed mitochondrion and got ‘tangled up‘
in the nucleus. In fact, organelle lysis and direct
DNA transfer – in theory and in practice – will
very efficiently drive gene transfer to the nucleus
over evolutionary time14,15. The c2mtch insertion
is a striking demonstration that whole organelle
genomes (with all of their genes) can integrate into
the nucleus.
Furthermore, c2mtch is 99% identical at the
nucleotide level to the authentic mitochondrial
genome, suggesting that transfer was recent12. Using
a rough molecular-clock guesstimate, if we assume
that the nuclear synonymous nucleotide substitution
rate in plants is about 5 × 10−9 per site per year16,
then a 1% divergence to the mitochondrial copy
indicates that the transfer of c2mtch occurred only
~2 million years ago. Of course, c2mtch is only one
data point and might be unique, or similar events
could have occurred in other higher-plant lineages
as well – data from other plant genomes will show
whether that is true. If we consider c2mtch as being
roughly representative of transfer from organelles
to the nucleus, then it would seem that an entire
plant mitochondrial genome gets transferred to
the nucleus at the rate of about once every 2 million
years – per plant species. That would be the kind
of continuous flux of bulk DNA from organelles
to the nucleus that would work in favour of the
mechanisms shown in Fig. 1b and, particularly,
Fig. 1c; recombination in the nucleus could supply
promoters, transit peptides and the rest.
If both editing and intron insertion in plant
mitochondrial DNA are indeed reversible processes
(and we are positing that they are), then bulk
transfer of the type documented in Arabidopsis
386 Opinion TRENDS in Genetics Vol.17 No.7 July 2001
c2mtch would also encompass (at some points in
evolutionary time) the transfer of transient states
in the mitochondrial genome. (In other words, a
gene in the mitochondrion that is edited and intron-
containing today might have been unedited and
intronless, say, 50 million years ago, and edited and
intron-containing 100 million years ago, etc.) Hence
it would be impossible to distinguish what state was
transferred (with or without intron, with or without
edited sites) by looking at contemporary plant
mitochondrial DNA.
Recombination
Transfer events of the type revealed by c2mtch
provide an inexhaustible source of genetic
material pouring into nuclear chromosomes –
the starting material for recombination, mutation
and new functions. Is there evidence for nuclear
recombination involving DNA derived from the
mitochondrion? Yes. Kadowaki et al.17 reported very
clear examples for the mitochondrial ribosomal
protein, Rps11. Rice has two recently duplicated
nuclear genes for Rps11 (Rps11-1 and Rps11-2),
in addition to an Rps11 pseudogene in the
mitochondrion. Both nuclear copies have N-terminal
transit peptides to direct the protein to the
organelle. In Rps11-1, part of the transit peptide was
acquired from the nuclear gene for mitochondrial
AtpB (a component of the ATPase) through
recombination, such that part of the same transit
peptide is found on two different nuclear genes,
Rps11-1 and AtpB. The transit peptide of Rps11-2
was taken from the nuclear gene for mitochondrial
cytochrome c oxidase subunit Vb, coxVB (Ref. 17).
Long et al.18 found that the transit peptide for
mitochondrial cytochrome c in potato was acquired
by nuclear exon shuffling between the transferred
gene for cytochrome c and a gene for glyceraldehyde-
3-phosphate dehydrogenase. Similarly,
recombination between the gene encoding Rps10
and genes encoding the heat shock proteins Hsp22
and Hsp70 was found in the more recent study2.
One of the most bizarre examples of Nature’s
ingenuity in recombining a mitochondrial gene
involves the mitochondrial ribosomal protein
Rps14 in rice19 and maize20. This mitochondrial
gene (rps14) has recombined into the intron of the
nuclear gene SDHB, which encodes the β-subunit
of succinate dehydrogenase – a mitochondrial
protein containing a transit peptide. To add to
the complexity, SDHB is itself a nuclear gene of
mitochondrial origin and is even encoded in some
mitochondrial genomes still21. To make matters
worse, through alternative splicing, the same
transit peptide encoded by a single nuclear locus
is used by two different mitochondrial proteins,
Rps14 and SdhB, in rice and maize20,21.
Finally, Kubo and colleagues22 found a striking
example in the rice genome that is convincing
evidence in favour of the view that relocation of
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mitochondrial genes to the nucleus involves the
transfer of bulk DNA and recombination, not cDNA.
The study found a piece of DNA from the rice
mitochondrion containing a fragment of the rps19
coding region, a fragment of the rps3 coding region
and a segment of the group II intron in the rps3 gene.
This DNA has made its way to the nucleus and
recombined into the 3′ region of a nuclear gene for a
vacuolar ATPase22. The hybrid gene is rather strongly
expressed as an mRNA, but it encodes nothing but
exquisite junk22 – half of the ATPase-coding region
is missing, the mitochondrial intron and coding
sequences are expressed in the antisense orientation,
and there is an unedited editing site left in the
mtDNA-derived sequence22. Clearly, as in the case
of Arabidopsis c2mtch, recombination involving a
piece of rice mtDNA, transferred as bulk DNA, not
as cDNA, was at work here22.
Summing up – looking back in time
There are plenty of interesting things to look for in
the Arabidopsis genome23. The first search for bits
of organelle DNA on the other four chromosomes
was less fruitful than the search of chromosome 2
because, in addition to the massive 620-kb c2mtch
insert12,13, only 11 other insertions of mitochondrial
DNA (totalling 7 kb) and 17 chloroplast insertions
(totalling 11 kb and including an intron) were found
using BLAST-based analyses23. But broad-scale
phylogenetic estimates indicate that several
hundred (perhaps even several thousand) active
and expressed Arabidopsis genes are acquisitions
from chloroplasts alone24.
Much current thinking about the mechanisms of
gene transfer from organelles to the nucleus focuses
on cDNA-mediated processes, perhaps because some
interesting examples suggest that this might be
true. And it might very well be true in some cases
but, as outlined here, alternative mechanisms can
account for the same observations where cDNA is
invoked. Well in advance of findings implicating
cDNA3–6, evidence for direct DNA transfer from
organelles to the nucleus was clear1,2. The presence
of an entire mitochondrial DNA genome in the
Arabidopsis nucleus12,13 (c2mtch) is a reminder
that direct DNA transfer certainly does occur and –
all things considered – probably constitutes the
general rule to which evolutionarily recent cases
of cDNA-mediated transfer in some higher plants
are exceptions.
After all, the majority of gene transfer from
organelles to the nucleus occurred during the early
stages of the integration of these organelles into the
cytosol of their host25,26. Both editing7 and the spread
of mitochondrial introns27 are comparatively recent
developments in the overall course of plant evolution.
Thus, there must have been a time in life’s history
when neither organellar editing nor organellar
introns existed. During that phase of evolution, the
transfer of bulk DNA and activation of genes through
 Opinion TRENDS in Genetics Vol.17 No.7 July 2001 387

recombination to yield promoter- and transit-peptide- the basis of the contribution of those cytosolic
bearing copies in the host cell’s chromosomes (Fig. 1b) gene products to the overall fitness of the cell. In
should have been the prevalent mechanism – a single that way, biochemical pathways once germane to
lysed organelle every few million years would more endosymbionts could have been transferred to the
than suffice. host’s cytosol through the simple relocation of the
And looking back one step further into the very corresponding genes30. In general agreement with
Acknowledgements earliest stages of organelle evolution, there must that reasoning, recent estimates suggest that about
We thank Koh-ichi have been a time when even the protein-import 600 Arabidopsis nuclear genes of cyanobacterial
Kadowaki (Tsukuba,
Japan) for kindly sharing
apparatus specific for these organelles28,29 had not (plastid) origin encode cytosolic proteins31. There
data before publication yet evolved. During that early phase of evolution, is still much to learn about gene transfer from
and Volker Knoop (Ulm, transit peptides were absent. Hence, genes that organelles, both in terms of mechanisms and terms
Germany) for discussions.
were transferred from endosymbionts to the of how it has shaped the contours of eukaryotic
Work in the authors’s lab
is funded by the DFG and chromosomes of their host would have been genomes – even the genomes of eukaryotes that
by SFB-TR/1. expressed only in the cytosol, and fixed only on have lost their organelles32!
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